Gene expression profiling in hypertrophied heart as the determinant of phenotype of heart failure

肥厚心脏的基因表达谱作为心力衰竭表型的决定因素

• 批准号: 15590742
• 负责人: YAMAMOTO Kazuhiro
• 金额: $ 2.05万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590742/
• 关键词: Heart Failure; Cardiac Hypertrophy; Remodeling

We analyzed gene expression pattern in hypertensive heart using Dahl salt-sensitive rats with diastolic heart failure or systolic heart failure. Expression profiling of mRNA reveals several clusters in approximate 8000 genes using cDNA array method for heart tissue of those different phenotypes of heart failure.Enhancement of gene expression and activity of matrix metalloproteinases (MMPs ) preceded LV dilatation in a hypertensive heart failure model. Angiotensin converting enzyme (ACE) inhibition suppressed the preceding activation of MMPs and prevented LV remodeling and dysfunction. MMPs are likely to trigger LV remodeling. ACE inhibition directly inhibits MMPs, leading to prevention of heart failure in hypertensive heart. We also analyzed the effects of angiotensin II type 1 receptor Mocker (ARB) and angiotensin converting enzyme inhibitor (ACED on the synthesis and degradation of collagens in a rat model of diastolic heart failure (DHF). Their administration similarly inhibited ventricular fibrosis. The ACEI administration decreased type I collagen mRNA level, but the decrease was less than that induced by the ARB administration. ARB and ACEI inhibited ventricular fibrosis through different mechanisms in DHF. ARB added to ACEI provides more benefits as compared with ACEI alone in DHF when initiated at advanced stage. The additive effects are likely provided through more prominent suppression of ROS generation and inflammatory changes without effects on expression of MCP-1 and TNF-alpha.N-methylethanolamine (MEA) may exert therapeutic effects on cardiac disorders due to ventricular fibrosis through suppression of phospholipase D (PLD) activity and modulation of fibrosis pathway even without a release from mechanical stress.

我们使用患有舒张性心力衰竭或收缩性心力衰竭的 Dahl 盐敏感大鼠分析了高血压心脏的基因表达模式。使用 cDNA 阵列方法对不同心力衰竭表型的心脏组织进行 mRNA 表达谱分析，揭示了大约 8000 个基因中的几个簇。在高血压心力衰竭模型中，基质金属蛋白酶 (MMP) 的基因表达和活性增强先于 LV 扩张。血管紧张素转换酶 (ACE) 抑制抑制了 MMP 的先前激活，并防止左心室重塑和功能障碍。 MMP 可能会引发左心室重塑。 ACE 抑制直接抑制 MMP，从而预防高血压心脏的心力衰竭。我们还分析了血管紧张素 II 1 型受体 Mocker (ARB) 和血管紧张素转换酶抑制剂 (ACED) 对舒张性心力衰竭 (DHF) 大鼠模型中胶原蛋白合成和降解的影响。它们的给药同样能抑制心室纤维化。施用降低了 I 型胶原 mRNA 水平，但降幅小于 ARB 施用引起的降幅，并且 ARB 和 ACEI 通过添加 DHF 中的不同机制抑制心室纤维化。与单独使用 ACEI 相比，在晚期开始治疗 DHF 时，ACEI 可以提供更多益处，其附加作用可能是通过更显着地抑制 ROS 生成和炎症变化而提供，而不影响 MCP-1 和 TNF-α.N-甲基乙醇胺的表达。 MEA）可以通过抑制磷脂酶 D (PLD) 活性和调节纤维化途径，对心室纤维化引起的心脏疾病发挥治疗作用，即使没有释放机械应力。

项目成果

AT1 receptor Mocker added to ACE inhibitor provides benefits at advanced stage of hypertensive diastolic heart failure.

AT1 受体 Mocker 添加到 ACE 抑制剂中，可为高血压舒张性心力衰竭晚期患者带来益处。

• 发表时间: 2004
• 期刊: Hypertension 43(3)
• 作者: Kazuhiro Yamamoto;Junichi Yoshida
• 通讯作者: Junichi Yoshida

ACE inhibitor and angiotensin II type 1 receptor blocker differently regulate ventricular fibrosis in hypertensive diastolic heart failure

• DOI: 10.1097/00004872-200502000-00022
• 发表时间: 2005-02-01
• 期刊: JOURNAL OF HYPERTENSION
• 影响因子: 4.9
• 作者: Yamamoto, K;Mano, T;Masuyama, T
• 通讯作者: Masuyama, T

Junichi Yoshida: "AT1 RECEPTOR BLOCKER ADDED TO ACE INHIBITOR PROVIDES BENEFITS AT ADVANCED STAGE OF HYPERTENSIVE DIASTOLIC HEART FAILURE"Hypertension. in press. (2004)

Junichi Yoshida：“在 ACE 抑制剂中添加 AT1 受体阻滞剂可在高血压舒张性心力衰竭的晚期阶段提供益处”高血压。

AT1 Receptor Blocker Added to ACE Inhibitor Provides Benefits at Advanced Stage of Hypertensive Diastolic Heart Failure

• DOI: 10.1161/01.hyp.0000118017.02160.fa
• 发表时间: 2004-03
• 期刊: Hypertension: Journal of the American Heart Association
• 作者: Junichi Yoshida;Kazuhiro Yamamoto;T. Mano;Y. Sakata;N. Nishikawa;Mayu Nishio;T. Ohtani;T. Miwa;M. Hori;T. Masuyama

Activation of matrix metalloproteinases precedes LV remodeling in hypertensive heart failure rats : its inhibition as a primary effect of ACE inhibitor.

高血压心力衰竭大鼠中基质金属蛋白酶的激活先于左室重塑：其抑制是 ACE 抑制剂的主要作用。

• 发表时间: 2004
• 期刊: Circulation 109(17)
• 作者: Kazuhiro Yamamoto;Junichi Yoshida;Yasushi Sakata
• 通讯作者: Yasushi Sakata